Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes.
BACKGROUND
Dipeptidyl peptidase 4 (DPP-4) inhibitors are proposed to lower blood glucose in type 2 diabetes mellitus (T2DM) by prolonging the activity of the circulating incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Consistent with this mechanism of action, DPP-4 inhibitors improve glucose tolerance after meals by increasing insulin and reducing glucagon levels in the plasma. However, DPP-4 inhibitors also reduce fasting blood glucose, an unexpected effect because circulating levels of active GIP and GLP-1 are low in the postabsorptive state.


OBJECTIVE
The objective of the study was to examine the effects of DPP-4 inhibition on fasting islet function.


METHODS
We conducted a randomized, double-blind, placebo-controlled trial.


METHODS
The study was performed in General Clinical Research Centers at two University Hospitals.


METHODS
Forty-one subjects with T2DM were treated with metformin or diet, having good glycemic control with glycosylated hemoglobin values of 6.2-7.5%.


METHODS
Subjects were treated with vildagliptin (50 mg twice daily) or placebo for 3 months, followed by a 2-wk washout. Major Outcome Measure: We measured insulin secretion in response to iv glucose and arginine before and after treatment and after drug washout.


RESULTS
There were small and comparable reductions in glycosylated hemoglobin in both groups over 3 months. Vildagliptin increased fasting GLP-1 levels in subjects taking metformin, but not those managed with diet, and raised active GIP levels slightly. DPP-4 inhibitor treatment improved the acute insulin and C-peptide responses to glucose (50 and 100% respectively; P < 0.05) and increased the slope of the C-peptide response to glucose (33%; P = 0.023).


CONCLUSIONS
Vildagliptin improves islet function in T2DM under fasting conditions. This suggests that DPP-4 inhibition has metabolic benefits in addition to enhancing meal-induced GLP-1 and GIP activity.
D'Alessio
David A
DA
University of Cincinnati, Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, ML 0547, Cincinnati, Ohio 45267, USA. dalessd@ucmail.uc.edu
Denney
Amanda M
AM
Hermiller
Linda M
LM
Prigeon
Ronald L
RL
Martin
Julie M
JM
Tharp
William G
WG
Saylan
Monica Liqueros
ML
He
Yanling
Y
Dunning
Beth E
BE
Foley
James E
JE
Pratley
Richard E
RE
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D005215:Fasting / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects* / Q000503:physiopathology; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D000077597:Vildagliptin
D000218:Adamantane; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; C517652:hemoglobin A1c protein, human